Convergence of immune escape strategies highlights plasticity of SARS-CoV-2 spike DOI Creative Commons
Xiaodi Yu, Jarek Juraszek, Lucy Rutten

et al.

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(5), P. e1011308 - e1011308

Published: May 1, 2023

The global spread of the SARS-CoV-2 virus has resulted in emergence lineages which impact effectiveness immunotherapies and vaccines that are based on early Wuhan isolate. All currently approved employ spike protein S, as it is target for neutralizing antibodies. Here we describe two isolates with unusually large deletions N-terminal domain (NTD) spike. Cryo-EM structural analysis shows result complete reshaping NTD supersite, an antigenically important region NTD. For both variants remodeling negatively affects binding all tested NTD-specific antibodies outside supersite. one variants, observed a P9L mediated shift signal peptide cleavage site resulting loss disulfide-bridge; unique escape mechanism high antigenic impact. Although disulfide mutations rare, similar modifications have become independently established several other lineages, indicating possibility to more dominant future. plasticity foreshadows its broad potential immune continued SARS-CoV-2.

Language: Английский

Jointly modeling deep mutational scans identifies shifted mutational effects among SARS-CoV-2 spike homologs DOI Creative Commons
Hugh K. Haddox, Jared Galloway, Bernadeta Dadonaite

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 2, 2023

Deep mutational scanning (DMS) is a high-throughput experimental technique that measures the effects of thousands mutations to protein. These experiments can be performed on multiple homologs protein or same selected under conditions. It often biological interest identify with shifted across However, it challenging determine if observed shifts arise from signal noise. Here, we describe method for jointly inferring DMS while also identifying have in their among experiments. A key aspect our regularize inferred shifts, so they are nonzero only when strongly supported by data. We apply this measure how spike proteins SARS-CoV-2 variants (Delta, Omicron BA.1, and BA.2) affect cell entry. Most conserved between these homologs, but fraction markedly shifted. experimentally validate subset effects, confirm differences > 1,000-fold impact mutation spike-mediated viral infection spikes different variants. Overall, work establishes general approach comparing sets biologically important effects.

Language: Английский

Citations

13
Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics DOI Creative Commons
Nicholas J. Ose, Paul Campitelli, Tushar Modi

et al.

eLife, Journal Year: 2024, Volume and Issue: 12

Published: May 7, 2024

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into adaptations SARS-COV-2 spike (S) protein. With this approach, we first identified candidate adaptive polymorphisms (CAPs) SARS-CoV-2 S and assessed impact these CAPs through analysis. Not only have found that frequently overlap well-known functional sites, but also, using several different dynamics-based metrics, reveal critical allosteric interplay between binding sites human ACE2 (hACE2) interact far differently hACE2 site residues in open conformation compared closed form. In particular, CAP control state, suggesting an binding. also explored characteristic mutations strains find dynamic hallmarks potential effects future mutations. Our analyses Delta strain-specific variants non-additive (i.e., epistatic) interactions whereas less pathogenic Omicron mostly additive Finally, our analysis suggests novel observed strain epistatically help escape antibody

Language: Английский

Citations

4
Variation in structural motifs within SARS-related coronavirus spike proteins DOI Creative Commons

Francesca R. Hills,

Alice-Roza Eruera, James Hodgkinson-Bean

et al.

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(5), P. e1012158 - e1012158

Published: May 28, 2024

SARS-CoV-2 is the third known coronavirus (CoV) that has crossed animal-human barrier in last two decades. However, little structural information exists related to close genetic species within SARS-related coronaviruses. Here, we present three novel CoV spike protein structures solved by single particle cryo-electron microscopy analysis derived from bat (bat SL-CoV WIV1) and civet (cCoV-SZ3, cCoV-007) hosts. We report complex glycan trees decorate glycoproteins density for water molecules which facilitated modeling of molecule coordination networks structurally important regions. note conservation fatty acid binding pocket presence a linoleic are associated with stabilization receptor domains “down” conformation. Additionally, N-terminal biliverdin occupied all structures. Finally, analyzed differences loop motif between coronaviruses infect humans animal described this study, regulate human angiotensin converting enzyme 2 receptor. This study offers framework evaluate relatives SARS-CoV-2, ability inform pandemic prevention, aid development pan-neutralizing treatments.

Language: Английский

Citations

4
SARS-CoV-2 neutralizing antibody specificities differ dramatically between recently infected infants and immune-imprinted individuals DOI Creative Commons
Bernadeta Dadonaite, Allison Burrell,

Jenni Logue

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 20, 2025

The immune response to viral infection is shaped by past exposures related virus strains, a phenomenon known as imprinting. For SARS-CoV-2, much of the population has been imprinted spike from an early strain, either through vaccination or during stages COVID-19 pandemic. As consequence this imprinting, with more recent SARS-CoV-2 strains primarily boosts cross-reactive antibodies elicited imprinting strain. Here we compare neutralizing antibody specificities individuals versus infants infected Specifically, use pseudovirus-based deep mutational scanning measure how mutations affect neutralization serum adults and children original vaccine primary XBB* variant. While activity targets receptor-binding domain (RBD), only mostly N-terminal (NTD). In these infants, secondary exposure via shifts towards RBD, although specific RBD sites targeted are different than for adults. dramatic differences in among histories likely impact evolution.

Language: Английский

Citations

0
Genome data artifacts and functional studies of deletion repair in the BA.1 SARS-CoV-2 spike protein DOI Creative Commons
Miguel Álvarez-Herrera, Paula Ruiz-Rodríguez, Beatriz Navarro-Domínguez

et al.

Virus Evolution, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 1, 2025

Mutations within the N-terminal domain (NTD) of spike (S) protein are critical for emergence successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral lineages. The NTD has been repeatedly impacted by deletions, often exhibiting complex and dynamic patterns, such as recurrent disappearance deletions in dominant variants. This study investigates influence repair lineage-defining found BA.1 lineage (Omicron variant) on success. We performed comparative genomic analyses >10 million SARS-CoV-2 genomes from Global Initiative Sharing All Influenza Data (GISAID) EpiCov database to evaluate detection viruses lacking S:ΔH69/V70, S:ΔV143/Y145, or both. These findings were contrasted against a screening publicly available raw sequencing data, revealing substantial discrepancies between data repositories, suggesting that spurious deletion observations GISAID may result systematic artifacts. Specifically, events approximately an order magnitude less frequent read-run survey. Our results suggest rare, isolated with limited direct evolution transmission. Nevertheless, could facilitate fitness-enhancing mutations. To explore potential drivers we characterized phenotype markers surrogate vitro system. Repair S:ΔH69/V70 reduced infectivity, while simultaneous S:ΔV143/Y145 led lower fusogenicity. In contrast, individual enhanced both fusogenicity susceptibility neutralization sera vaccinated individuals. work underscores genotype-phenotype landscape SARS-CoV-2, which impacts biology, transmission efficiency, immune escape potential, offering insights relevance public health, surveillance, adaptive mechanisms driving emerging

Language: Английский

Citations

0
SARS-CoV-2 neutralizing antibody specificities differ dramatically between recently infected infants and immune-imprinted individuals DOI Creative Commons
Bernadeta Dadonaite, Allison Burrell,

Jenni Logue

et al.

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

ABSTRACT The immune response to viral infection is shaped by past exposures related virus strains, a phenomenon known as imprinting. For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), much of the population has been imprinted spike from an early strain, either through vaccination or during stages COVID-19 pandemic. As consequence this imprinting, with more recent SARS-CoV-2 strains primarily boosts cross-reactive antibodies elicited imprinting strain. Here we compare neutralizing antibody specificities individuals versus infants infected Specifically, use pseudovirus-based deep mutational scanning measure how mutations affect neutralization serum adults and children original vaccine primary XBB* variant. While activity targets receptor-binding domain (RBD), only mostly N-terminal domain. In these infants, secondary exposure via shifts toward RBD, although specific RBD sites targeted are different adults. dramatic differences in among histories likely impact evolution. IMPORTANCE We show that person’s history strongly affects which regions on their target. particular, who have just once strain make target than exposed both older strains. This person-to-person heterogeneity means same mutation can impacts immunity people.

Language: Английский

Citations

0
Rapid Detection of SARS-CoV-2 RNA Using Reverse Transcription Recombinase Polymerase Amplification (RT-RPA) with Lateral Flow for N-Protein Gene and Variant-Specific Deletion–Insertion Mutation in S-Protein Gene DOI Creative Commons
J. L. Granda, Mónica J. Pajuelo, Michiko Okamoto

et al.

Viruses, Journal Year: 2023, Volume and Issue: 15(6), P. 1254 - 1254

Published: May 26, 2023

Rapid molecular testing for severe acute respiratory coronavirus 2 (SARS-CoV-2) variants may contribute to the development of public health measures, particularly in resource-limited areas. Reverse transcription recombinase polymerase amplification using a lateral flow assay (RT-RPA-LF) allows rapid RNA detection without thermal cyclers. In this study, we developed two assays detect SARS-CoV-2 nucleocapsid (N) gene and Omicron BA.1 spike (S) gene-specific deletion–insertion mutations (del211/ins214). Both tests had limit 10 copies/µL vitro time was approximately 35 min from incubation detection. The sensitivities RT-RPA-LF by viral load categories were 100% clinical samples with high (>9015.7 copies/µL, cycle quantification (Cq): < 25) moderate (385.5–9015.7 Cq: 25–29.9) load, 83.3% low (16.5–385.5 30–34.9), 14.3% very (<16.5 35–40). 94.9%, 78%, 23.8%, 0%, respectively, specificity against non-BA.1 SARS-CoV-2-positive 96%. seemed more sensitive than antigen samples. Although implementation settings requires additional improvements, successfully detected technique.

Language: Английский

Citations

10
Defining neutralization and allostery by antibodies against COVID-19 variants DOI Creative Commons
Nikhil Kumar Tulsian,

Raghuvamsi Venkata Palur,

Xinlei Qian

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 1, 2023

The changing landscape of SARS-CoV-2 Spike protein is linked to the emergence variants, immune-escape and reduced efficacy existing repertoire anti-viral antibodies. functional activity neutralizing antibodies their quaternary changes occurring as a result antibody-Spike trimer interactions. Here, we reveal conformational dynamics allosteric perturbations binding novel human viral protein. We identified epitope hotspots, associated in that distinguish weak, moderate strong show impact mutations Wuhan-Hu-1, Delta, Omicron variants on differences antibody-induced illustrate how these render certain ineffective. Antibodies with similar affinities may induce destabilizing or stabilizing effects Spike, implications for neutralization efficacy. Our results provide mechanistic insights into modes synergistic behavior against COVID-19 assist designing effective antiviral strategies.

Language: Английский

Citations

10
Therapeutic antibodies and alternative formats against SARS-CoV-2 DOI Creative Commons
Rahel R. Winiger, Laurent Perez

Antiviral Research, Journal Year: 2024, Volume and Issue: 223, P. 105820 - 105820

Published: Feb. 1, 2024

The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) heavily burdened the entire world. Despite a prompt generation of vaccines and therapeutics to confront infection, virus remains threat. ancestor viral strain has evolved into several variants concern, with Omicron variant now having many distinct sublineages. Consequently, most available antibodies targeting spike went obsolete thus new therapies or therapeutic formats are needed. In this review we focus on antibody targets, provide an overview progress made so far, describe novel being explored, lessons learned from that can enhance preparedness.

Language: Английский

Citations

3
Emergence of SARS-CoV-2 Omicron Variant JN.1 in Tamil Nadu, India - Clinical Characteristics and Novel Mutations DOI Creative Commons

Sivaprakasam T. Selvavinayagam,

Sathish Sankar, Yean K. Yong

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 19, 2024

In December 2023, we observed a notable shift in the COVID-19 landscape, when JN.1 emerged as predominant SARS-CoV-2 variant with 95% incidence. We characterized clinical profile, and genetic changes JN.1, an emerging of interest. Whole genome sequencing was performed on positive samples, followed by sequence analysis. Mutations within spike protein sequences were analyzed compared previous lineages sublineages SARS-CoV-2, to identify potential impact these unique mutations structure possible functionality. Several dynamic identified herein. Our data provides key insights into emergence newer variants our region highlights need for robust sustained genomic surveillance SARS-CoV-2.

Language: Английский

Citations

3